PINK1-PRKN Mediated Mitophagy

PINK1-PRKN Mediated Mitophagy This is the process of selective removal of damaged mitochondria by autophagosomes and subsequent catabolism by lysosomes. In healthy mitochondria, PTEN-induced putative kinase 1 (PINK1) is imported to the inner mitochondrial membrane, presumably through the TOM/TIM complex. The TIM complex associated protease, mitochondrial MPP, cleaves PINK1 mitochondrial targeting sequence (MTS). PINK1 may be cleaved by the inner membrane presenilin-associated rhomboid-like protease (PARL) and ultimately proteolytically degraded. Loss of membrane potential in damaged mitochondria prevents the import of PINK1 which accumulates on the mitochondrial outer membrane (MOM) of the defective mitochondria. Activation of PINK1 at MOM is achieved via dimerization-mediated trans-autophosphorylation of PINK1 at multiple sites including S228 and S402 (Okatsu K et al., 2012, 2013; Aerts L et al., 2015; Rasool S et al., 2018, 2022; Gan ZY et al., 2022). Activated PINK1 phosphorylates S65 of ubiquitin (Ub) on MOM proteins which leads to increased recruitment of the E3 ubiquitin ligase Parkin (PRKN) to damaged mitochondria (Koyano F et al., 2014; Shiba-Fukushima K et al., 2014; Ordureau A et al., 2015). Activated PINK1 also phosphorylates PRKN at S65 in the N-terminal Ub-like domain inducing the E3 ligase activity of PRKN (Kondapalli et al., 2012; Kazlauskaite A et al., 2015; Ordureau A et al., 2015). Activated PRKN promotes the ubiquitination of mitochondrial substrates including mitofusin 1 and 2 (MFN1, 2) and the voltage-dependent anion channel 1 and 3 (VDAC1, 3). The E3 ligase activity of PRKN generates Ub moieties for PINK1-mediated phosphorylation of Ub thus leading to a feedforward loop in the PINK1:PRKN pathway (Ordureau A et al., 2015; Sauve V et al., 2022). Ubiquitin chains on PRKN-ubiquitinated substrates recruit cargo receptors such as SQSTM1 (p62) and OPTN linking the ubiquitinated substrates to the microtubule-associated proteins 1A/1B light chain 3 (LC3, MAP1LC3) (Heo LM et al., 2015; Lazarou M et al., 2015). The recruitment of both MAP1LC3 (LC3) complexes and the autophagy proteins 5 and 12 (Atg5: Atg12) complex to the autophagosome membrane promotes autophagosome formation. The mitochondrion is engulfed after the isolation membrane grows to a sufficient size to engulf the mitochondrion. Once autophagic vesicle formation is complete, vesicle fusion with lysosomes occurs to form autophagolysosomes in which the lysosomal hydrolases (cathepsins and lipases) degrade the intra autophagosomal content. Cathepsin also degrades LC3 on the intra autophagosomal surface of the autophagic vesicle.